HUMAN iNKT CELL ACTIVATION USING GLYCOLIPIDS WITH ALTERED GLYCOSYL GROUPS

Patent metadata

Field	Value
Publication number	US-2019099486-A1
Application number	US-201816175504-A
Country	US
Kind code	A1
Filing date	Oct 30, 2018
Priority date	Sep 6, 2013
Publication date	Apr 4, 2019
Grant date	—

Abstract

Glycosphingolipids (GSLs) bearing α-glucose (α-Glc) that preferentially stimulate human invariant NKT (iNKT) cells are provided. GSLs with α-glucose (α-Glc) that exhibit stronger induction in humans (but weaker in mice) of cytokines and chemokines and expansion and/or activation of immune cells than those with α-galactose (α-Gal) are disclosed. GSLs bearing α-glucose (α-Glc) and derivatives of α-Glc with F at the 4 and/or 6 positions are provided. Methods for iNKT-independent induction of chemokines by the GSL with α-Glc and derivatives thereof are disclosed. Methods for immune stimulation in humans using GSLs with α-Glc and derivatives thereof are provided.

First claim

What is claimed is:

1 . An immune adjuvant compound having Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is —OH or halogen;
R 2 is —OH, or halogen;
R 3 is hydrogen;
each instance of R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, or optionally substituted acyl;
n is an integer of 1 to 15, inclusive;
m is an integer of 1 to 20, inclusive;
wherein at least one of R 1 or R 2 is halogen.

2 . The compound of claim 1 , wherein R 2 is —OH.

3 . The compound of claim 1 , wherein R 1 is —OH.

4 . The compound of claim 1 , wherein R 1 is halogen.

5 . The compound of claim 1 , wherein R 4 is of Formula (II):

wherein:
i is 0, 1, 2, 3, 4, or 5;
R 6 is independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, or optionally substituted acyl.

6 . The compound of claim 5 , wherein R 6 is halogen.

7 . The compound of claim 5 , wherein R 6 is F.

8 . The compound of claim 1 , wherein R 4 is of Formula (III):

wherein:
j is 0, 1, 2, 3, or 4;
k is 0, 1, 2, 3, 4, or 5;
each instance of R 7 and R 8 is independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, or optionally substituted acyl.

9 . The compound of claim 8 , wherein each instance of R 7 and R 8 is independently hydrogen or halogen.

10 . The compound of claim 8 , wherein R 7 is hydrogen; R 8 is F; and k is 1, 2 or 3.

11 . The compound of claim 8 , wherein R 7 is F; R 8 is hydrogen; and j is 1, 2 or 3.

12 . The compound of claim 8 , wherein R 7 and R 8 both are F; k is 1, 2 or 3; and j is 1, 2 or 3.

13 . The compound of claim 1 , wherein the compound is selected from one of the following:

14 . A pharmaceutical composition comprising: (i) a compound according to any of claims 1 - 13 in an amount sufficient to stimulate an immune response when co-administered with an antigen to a human subject, and (ii) a pharmaceutically acceptable excipient.

15 . A method for augmenting an immunogenicity of an antigen in a subject in need thereof, comprising co-administering said antigen with an adjuvant composition comprising a GSLs compound of the general Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is —OH or halogen;
R 2 is —OH, or halogen;
R 3 is hydrogen;
each instance of R 4 and R 5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, or optionally substituted acyl;
n is an integer of 1 to 15, inclusive;
m is an integer of 1 to 20, inclusive;
wherein at least one of R 1 or R 2 is halogen.

16 . A method for stimulating an immune response in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of an immune adjuvant composition in a pharmaceutically acceptable carrier, wherein the composition comprises a compound according to any of claims 1 - 13 .

17 . The method of claim 15 , wherein the adjuvant composition is a vaccine adjuvant.

18 . The method of claim 15 , wherein the adjuvant composition is administered in amount capable of elevating invariant Natural Killer T (iNKT) cells in humans.

19 . The method of claim 18 , wherein administration of the adjuvant composition increases cytokine and/or chemokine production in humans.

20 . The method of claim 19 , wherein the cytokine production is sufficient to transactivate downstream immune cells.

21 . The method of claim 20 , wherein the downstream immune cells comprise one or more of dendritic cells (DC), natural killer cells (NK), B cells, CD4 + T and CD8 + T cells.

22 . The method of claim 21 , wherein the cytokines comprise Th1 cytokines.

23 . The method of claim 22 , wherein the Th1 cytokines is selected from at least one of the group comprising: interferon-gamma (IFN-γ), GM-CSF, TNFα, interleukin 2, interleukin 12 and interleukin 10.

24 . The method of claim 19 , wherein the chemokine is selected from at least one of the group comprising RANTES, MIP-1α, KC, MCP-1, IP-10 and MIG.

25 . The method of claim 15 , wherein administration of the composition has an anti-cancer effect.

26 . The method of claim 25 , wherein the cancer is selected from the group consisting of lung cancer, breast cancer, hepatoma, leukemia, solid tumor and carcinoma.

27 . The method of claim 15 , wherein R 4 in the compound of Formula I is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and wherein increase in Th1 cytokines in humans exceeds any increase in Th2 cytokines.

28 . A method for elevating invariant Natural Killer T (iNKT) cells production in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the composition comprises a compound according to any of claims 1 - 13 .

29 . A method for stimulating cytokine and/or chemokine production in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the composition comprises a compound according to any of claims 1 - 13 in an amount sufficient to increase cytokine/chemokine production.

30 . The method of cla

Assignees

• Academia Sinica

Inventors

• Wong Chi-Huey
• Yu Alice L
• Lin Kun-Hsien
• Wu Tai-Na

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P31/12

  Antivirals · CPC title